The primary goal of this Program Project is to investigate interactions between the aging brain and female reproductive senescence. Early studies in young female rats demonstrated clearly that changes in circulating estrogen (E) levels affect cellular and molecular attributes of hypothalamic circuits as well as hippocampus, implicating E in modulating both reproductive neuroendocrine circuits and cognition. However, we now know that the aged brain reacts to E differently than the young brain, and we also know that the estrogen/aging interactions differ in important ways between rodents and nonhuman primates. The key to the next five years is to use both animal models to their best advantage to provide a neurobiological framework for the complex clinical issues surrounding the neurobiology of menopause and post-menopausal cognitive impairment. We will pursue a full spectrum analysis of the key issues;from signaling mechanisms of estrogen to an in-depth structural and functional assessment of the effects of estrogen on the circuits regulating reproductive function (hypothalamus), and cognition (hippocampus and prefrontal cortex). We will continue to reveal the neuronal signaling pathways activated by circulating E, as well as the molecular and synaptic basis for age related decline in E-induced synaptic plasticity. The rodent studies are particularly informative with respect to molecular mechanisms, and they have revealed several new targets of investigation for E signaling in hypothalamus, hippocampus and prefrontal cortex. The nonhuman primate studies reveal the neurobiological underpinnings of E-induced cognitive enhancement in aged monkeys, as well as the synaptic basis of cognitive resilience in the absence of E in young female monkeys. In addition, the nonhuman primate studies have highlighted the importance of prefrontal cortex and related cognitive functions as a target for E. Current studies in both the rat and nonhuman primate models are investigating the cognitive and neurobiological effects of different hormone treatment regimens. Proposed studies will investigate the "window of opportunity" hypothesis and the duration of beneficial effects after cessation of treatment. These results will provide critically important information on brain aging and will aid in the design of hormone treatments that provide maximal neurological benefits for post-menopausal women. PUBLIC HEALTH RELEVANCE: Currently American women can expect to live nearly half of their adult life post-menopause. Given the importance of the brain as a target organ for estrogen, it is not surprising that many of the complaints that prompt women to seek treatment at menopause are neurological in origin. The proposed studies will lead to more successful hormone treatments for menopausal women that maximize beneficial effects to the brain and minimize potential risks. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: THE NONHUMAN PRIMATE CORE;Dr. Bill Lasley, Core Leader (CL) DESCRIPTION (provided by applicant): The Animal Core is essential for the extension of the concepts that have been developed during the previous funding periods. In this application the Animal Core continues to provide the unique nonhuman primate (NHP) animal model, a trained staff in NHP research as well as specific methodologies and services that are required to make appropriate and efficient use of this limited resource. Studies involving monkeys currently in protocol will be completed in early 2011 and additional aged female rhesus monkeys will enter protocols and be studied over the five-year funding period. Our current data demonstrate the importance of estrogen treatment (ET) for the maintenance of higher brain function and structure in the absence of normal ovarian function in aged female primates. However, these previous studies have not conclusively identified which modality of ET or combined hormone treatment (HT) regimens are most effective and specifically which effective modalities would be best for clinical applications. The monkeys currently in protocol are committed to these studies. The monkeys that will enter protocols over this funding period will be used to investigate the structural and functional repercussions of altering the time of onset and duration of treatment following ovariectomy (OVX). These studies will investigate two critically important clinical issues;1) Is there a "window of opportunity" following cessation of ovarian function after which the brain is less responsive to ET/HT, and 2) Do the cognitive benefits of ET/HT started soon after the loss of circulating sex steroids persist after treatment is halted? Resources provided by the Animal Core include clinical care, trained animal care staff, therapeutic support, surgery/necropsy services and endocrine services. In addition, the California National Primate Center (CNPRC) behavior and endocrine staff scientists have participated in the design of the experiments and will be involved in the execution of the total research plan. Appropriately, the current application addresses specific questions that cannot be ethically approached in clinical studies but are effectively addressed in a NHP model. These studies will provide new and important information and insights for designing critical studies in the future. In addition, the results from all of the experiments will have direct and important implications for improved therapies to insure healthy aging in women. Both the use of the NHP model and a Primate Center setting and staff are required in order to effectively conduct such experiments and guarantee the delivery of interpretable data. PUBLIC HEALTH RELEVANCE: The use of the nonhuman primate animal model is considered essential for investigations relating to the role of ovarian hormones in human aging and only a primate center facility and staff can provide the necessary resources and skills to conduct such studies. One of the most pressing issues in women's health is the efficacy and safety of estrogen replacement therapy for menopausal symptoms and cognitive health. This application provides the plan, resources and the expertise to conduct studies that address this issue.